Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.063
Paulina Horvei M.D. , Jonathan Li MD , Franziska Rosser MD, MPH , Kirsten Rose-Felker MD , Jessie L Alexander MD, MSCR , Nicole Hogue PA-C , Shawna McIntyre BSN RN , Lauren Koshy PT , Adam Olson MD , Kathryn Torok MD , Paul Szabolcs MD
<div><h3>Objectives</h3><div>Juvenile-onset systemic sclerosis (jSSc) is a rare autoimmune disease characterized by vasculopathy and multiorgan fibrosis, leading to significant morbidity and early mortality. Autologous stem cell transplantation (ASCT) is an emerging treatment for refractory adult SSc, but data in jSSc are limited. We report outcomes of eight consecutive patients with refractory jSSc treated with ASCT at a single center.</div></div><div><h3>Methods</h3><div>Patients with moderate-to-severe disease jSSc refractory to ≥3 DMARDs were referred to our multidisciplinary pediatric scleroderma center, if deemed appropriate and eligible by the care team they underwent mobilization, apheresis and CD34+ selection, followed by conditioning regimen and stem cell transplants per FDA- and IRB-approved treatment plans (Patients 1–3) or clinical trial NCT03630211 (Patients 4–8). Clinical outcomes and patient reported measures were collected pre-ASCT and at 6-month intervals post-ASCT for up to four years.</div></div><div><h3>Results</h3><div>Eight patients with jSSc received ASCT and had at least 6 months of follow-up (median of 30 months). Median age of disease onset was 12.5 years and age at ASCT was 18 years. Most were female (75%). Median mRSS 23.5. All subjects had respiratory involvement, either from ILD (75%) and/or myopathy (median FVC 63%, DLCO 49% and 6MWT 51% predicted). Two had pulmonary arterial hypertension. All had moderate-to-severe GI involvement, Raynaud's phenomena, and most had digital pitting & ulceration. Six had moderate-to-severe joint contractures. Myositis was present in seven patients.</div><div>They all had disease refractory to >3 DMARDs and met criteria for ASCT by severity and/or continued activity of lung, skin or musculoskeletal disease. All patients would have either not met inclusion criteria or met exclusion criteria for the ASTIS and SCOT trial.</div><div>Most patients achieved successful apheresis after one day. Overall conditioning was well tolerated. All patients engrafted successfully. Median neutrophil and platelet engraftment was 13 and 22 days, respectively. There were no treatment-related deaths, life-threatening infections, or major organ toxicities. We observed delayed immune reconstitution consistent with intensive immunoablation and prior therapies, with T-cell expansion by 6 months and T & B cell immune reconstitution generally achieved by 12 and 6 months, respectively. Overall survival and event free survival is 100%. mRSS improved by a median of 93%, and 6-MWT by 13%. Seven patients discontinued immunosuppression. Gastrointestinal manometry improved in six patients. Pulmonary function stabilized, and both patients with pulmonary hypertension showed normalization of pressures. Global function, quality of life, and performance scores improved.</div></div><div><h3>Conclusions</h3><div>ASCT was safe and effective in this cohort of refractory jSSc patients, with sustained multisystem improv
{"title":"Autologous Stem Cell Transplantation for Refractory Juvenile-Onset Systemic Sclerosis","authors":"Paulina Horvei M.D. , Jonathan Li MD , Franziska Rosser MD, MPH , Kirsten Rose-Felker MD , Jessie L Alexander MD, MSCR , Nicole Hogue PA-C , Shawna McIntyre BSN RN , Lauren Koshy PT , Adam Olson MD , Kathryn Torok MD , Paul Szabolcs MD","doi":"10.1016/j.jtct.2025.12.063","DOIUrl":"10.1016/j.jtct.2025.12.063","url":null,"abstract":"<div><h3>Objectives</h3><div>Juvenile-onset systemic sclerosis (jSSc) is a rare autoimmune disease characterized by vasculopathy and multiorgan fibrosis, leading to significant morbidity and early mortality. Autologous stem cell transplantation (ASCT) is an emerging treatment for refractory adult SSc, but data in jSSc are limited. We report outcomes of eight consecutive patients with refractory jSSc treated with ASCT at a single center.</div></div><div><h3>Methods</h3><div>Patients with moderate-to-severe disease jSSc refractory to ≥3 DMARDs were referred to our multidisciplinary pediatric scleroderma center, if deemed appropriate and eligible by the care team they underwent mobilization, apheresis and CD34+ selection, followed by conditioning regimen and stem cell transplants per FDA- and IRB-approved treatment plans (Patients 1–3) or clinical trial NCT03630211 (Patients 4–8). Clinical outcomes and patient reported measures were collected pre-ASCT and at 6-month intervals post-ASCT for up to four years.</div></div><div><h3>Results</h3><div>Eight patients with jSSc received ASCT and had at least 6 months of follow-up (median of 30 months). Median age of disease onset was 12.5 years and age at ASCT was 18 years. Most were female (75%). Median mRSS 23.5. All subjects had respiratory involvement, either from ILD (75%) and/or myopathy (median FVC 63%, DLCO 49% and 6MWT 51% predicted). Two had pulmonary arterial hypertension. All had moderate-to-severe GI involvement, Raynaud's phenomena, and most had digital pitting & ulceration. Six had moderate-to-severe joint contractures. Myositis was present in seven patients.</div><div>They all had disease refractory to >3 DMARDs and met criteria for ASCT by severity and/or continued activity of lung, skin or musculoskeletal disease. All patients would have either not met inclusion criteria or met exclusion criteria for the ASTIS and SCOT trial.</div><div>Most patients achieved successful apheresis after one day. Overall conditioning was well tolerated. All patients engrafted successfully. Median neutrophil and platelet engraftment was 13 and 22 days, respectively. There were no treatment-related deaths, life-threatening infections, or major organ toxicities. We observed delayed immune reconstitution consistent with intensive immunoablation and prior therapies, with T-cell expansion by 6 months and T & B cell immune reconstitution generally achieved by 12 and 6 months, respectively. Overall survival and event free survival is 100%. mRSS improved by a median of 93%, and 6-MWT by 13%. Seven patients discontinued immunosuppression. Gastrointestinal manometry improved in six patients. Pulmonary function stabilized, and both patients with pulmonary hypertension showed normalization of pressures. Global function, quality of life, and performance scores improved.</div></div><div><h3>Conclusions</h3><div>ASCT was safe and effective in this cohort of refractory jSSc patients, with sustained multisystem improv","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S39-S40"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.064
Christen L. Ebens MD, MPH , Susie Long PharmD , Amanda K Johnson MD, MPH , Qing Cao MS
<div><h3>Introduction</h3><div>Fludarabine (Flu) is ubiquitous in conditioning for allogeneic hematopoietic cell transplant (HCT) for inborn errors of immunity (IEI). Optimal dosing is critical, with overexposure associated with delayed immune reconstitution and underexposure with increased graft failure. Many inborn errors of immunity require HCT in infancy making chemotherapy dosing more challenging given age-based variation in organ function and drug metabolism. Historically, Flu dosing was linear, based on body surface area (BSA) with an arbitrary weight-based dosing for the smallest patients. Development of a non-linear mixed-effects population pharmacokinetic (pop-PK) model incorporating creatinine clearance and actual body weight and subsequent identification of an optimal cumulative area-under-the-curve (cAUC) of 20 mg*hour/L (range 18-22) for non-malignant disease transplant outcomes is changing clinical practice.</div></div><div><h3>Objectives</h3><div>To investigate associations between Flu exposure and transplant outcomes in a cohort of patients with IEI who underwent HCT from 9/2012 to 9/2022.</div></div><div><h3>Methods</h3><div>We applied a pop-PK model (Brooks JT, et al., 2022, <em>Pharmaceutics</em>, 14(11):2462) to retrospectively estimate Flu exposure (cAUC) and categorized Flu conditioning as underexposed (cAUC <18 mg*hour/L), appropriate (18-22 mg*hour/L), or overexposed (>22 mg*hour/L). We recorded Flu dosing strategy used (by BSA or weight), occurrence of primary or secondary graft failure, status of immune reconstitution at day +100 by absolute CD4 count (appropriate if achievement of the first of two consecutive CD4 counts exceeded 50/uL or delayed if <50), and 2-year event-free survival (EFS, events included graft failure and death). Comparison of categorical variables was by Fisher’s exact test.</div></div><div><h3>Results</h3><div>The cohort included 37 patients: 25 recipients of reduced toxicity myeloablative conditioning (alemtuzumab, busulfan, fludarabine) and 12 recipients of reduced intensity conditioning (alemtuzumab, melphalan, and fludarabine). Estimated Flu exposures included 11 underexposed (<18 mg*hour/L), 9 appropriately exposed (18-22 mg*hour/L), and 17 overexposed (>22 mg*hour/L). Overexposure was highly associated with dosing strategy, affecting 17 of 22 patients dosed by BSA and none dosed by weight (p<0.0001). Of the 37 patients, thirty-three survived to day +100 to assess immune reconstitution. Immune reconstitution was achieved by 88.9% (16 or 18) of those with a Flu cAUC of </=22 mg*hour/L compared to only 40% (6 of 15) with Flu overexposure (p=0.008). We did not find an association between Flu overexposure and 2-year EFS (p>0.999).</div></div><div><h3>Conclusions</h3><div>Confirmation of fludarabine over-exposure association with delayed immune reconstitution in a single-center retrospective cohort undergoing HCT for IEI provides further support for implementation of clinica
{"title":"Retrospective Application of Population Pharmacokinetic Model-Based Dosing for Fludarabine in Allogeneic Hematopoietic Cell Transplant for Inborn Errors of Immunity","authors":"Christen L. Ebens MD, MPH , Susie Long PharmD , Amanda K Johnson MD, MPH , Qing Cao MS","doi":"10.1016/j.jtct.2025.12.064","DOIUrl":"10.1016/j.jtct.2025.12.064","url":null,"abstract":"<div><h3>Introduction</h3><div>Fludarabine (Flu) is ubiquitous in conditioning for allogeneic hematopoietic cell transplant (HCT) for inborn errors of immunity (IEI). Optimal dosing is critical, with overexposure associated with delayed immune reconstitution and underexposure with increased graft failure. Many inborn errors of immunity require HCT in infancy making chemotherapy dosing more challenging given age-based variation in organ function and drug metabolism. Historically, Flu dosing was linear, based on body surface area (BSA) with an arbitrary weight-based dosing for the smallest patients. Development of a non-linear mixed-effects population pharmacokinetic (pop-PK) model incorporating creatinine clearance and actual body weight and subsequent identification of an optimal cumulative area-under-the-curve (cAUC) of 20 mg*hour/L (range 18-22) for non-malignant disease transplant outcomes is changing clinical practice.</div></div><div><h3>Objectives</h3><div>To investigate associations between Flu exposure and transplant outcomes in a cohort of patients with IEI who underwent HCT from 9/2012 to 9/2022.</div></div><div><h3>Methods</h3><div>We applied a pop-PK model (Brooks JT, et al., 2022, <em>Pharmaceutics</em>, 14(11):2462) to retrospectively estimate Flu exposure (cAUC) and categorized Flu conditioning as underexposed (cAUC <18 mg*hour/L), appropriate (18-22 mg*hour/L), or overexposed (>22 mg*hour/L). We recorded Flu dosing strategy used (by BSA or weight), occurrence of primary or secondary graft failure, status of immune reconstitution at day +100 by absolute CD4 count (appropriate if achievement of the first of two consecutive CD4 counts exceeded 50/uL or delayed if <50), and 2-year event-free survival (EFS, events included graft failure and death). Comparison of categorical variables was by Fisher’s exact test.</div></div><div><h3>Results</h3><div>The cohort included 37 patients: 25 recipients of reduced toxicity myeloablative conditioning (alemtuzumab, busulfan, fludarabine) and 12 recipients of reduced intensity conditioning (alemtuzumab, melphalan, and fludarabine). Estimated Flu exposures included 11 underexposed (<18 mg*hour/L), 9 appropriately exposed (18-22 mg*hour/L), and 17 overexposed (>22 mg*hour/L). Overexposure was highly associated with dosing strategy, affecting 17 of 22 patients dosed by BSA and none dosed by weight (p<0.0001). Of the 37 patients, thirty-three survived to day +100 to assess immune reconstitution. Immune reconstitution was achieved by 88.9% (16 or 18) of those with a Flu cAUC of </=22 mg*hour/L compared to only 40% (6 of 15) with Flu overexposure (p=0.008). We did not find an association between Flu overexposure and 2-year EFS (p>0.999).</div></div><div><h3>Conclusions</h3><div>Confirmation of fludarabine over-exposure association with delayed immune reconstitution in a single-center retrospective cohort undergoing HCT for IEI provides further support for implementation of clinica","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S40-S41"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.042
Allison O. Taylor MD, MS , Sanghee Hong MD , Salene Jones PhD , Kevin Ng MS , Ted A. Gooley PhD , Neel Bhatt MBBS, MPH , Elizabeth M. Hellewell BS , Anthony D Sung MD , Nausheen Ahmed MD , Cherie Morey NP , Sarah Fitzmaurice NP , Vanessa E Kennedy MD , Michelle Lauer PA-C, MPH , Ami J. Shah MD , Andrew D. Trunk MD , Betty K. Hamilton MD , Akshay Sharma MBBS, MSc , Zoey Phelps-Bergeron PA-C , LaQuisa C. Hill MD , Rawan Faramand MD , Catherine J. Lee MD, MS
Introduction
Social drivers of health (SDOH) are associated with inequities in healthcare. We report the associations between SDOH on clinicians’ adherence to post HCT survivorship screening guidelines.
Methods
We conducted a retrospective, multi-center cohort study of HCT survivors from 22 US centers transplanted in 2016, disease free ≥ 3 years post HCT. Zip-code derived SDOH variables were obtained from the US Census (Table 1). Patient, disease and transplant characteristics, and late effects screening (breast, cervical, skin, DEXA, vitamin D, HgbA1c, fasting glucose, echo, renal, lipid, thyroid and dental) were abstracted from the EMR. Clinician adherence was defined as order/test completion 11 months-2 yrs post HCT. Logistic regression evaluated the relationship between SDOH and clinician adherence. SDOH factors were modeled as continuous linear variables, with the corresponding odds ratio (OR) presented for each 10% proportional increase in the SDOH factor.
Results
Of 500 pts [≤ 39 yrs (n=212); > 39 yrs (n=288)], SDOH variables were available for 374 pts. Median age at HCT was 47 yrs (interquartile range/IQR 21-60). 58% were male, 83% were White and 12% were Hispanic (Table 2).
Decreased cervical cancer screening was associated with less than a high school diploma (0.29, 0.09-0.95, p=0.04). Less DEXA testing occurred with increased internet access (0.86, 0.76-0.98, p=0.03) while renting increased screening (1.12,1.02-1.32, p=0.03). Vitamin D screening increased with increase in supplemental security income/SSI (2.63, 1.20-5.80, p=0.02) and having no cars (1.67, 1.07-2.59, p=0.02). Fasting glucose screening was associated with direct purchase insurance (DPI) (1.69,1.03-2.77, p=0.04) and renting (1.21,1.04-1.41, p=0.02) while increased internet access decreased screening (0.83, 0.71-0.96, p=0.02). Increased lipid screening was associated with DPI (2.33, 1.42-3.81, p<0.01) but decreased in pts below the poverty line (0.71, 0.53-0.94 p=0.02) and with less than a high school diploma (0.71, 0.55-0.91, p=0.01). Renal screening correlated with increase in SSI (3.17, 1.31-7.66, p=0.01), Medicaid enrollment (1.37, 1.08-1.73, p=0.01), and having no cars (1.75,1.07-2.88 p=0.03).
Conclusion
While SDOH were not statistically significantly associated with clinician adherence to HgbA1c, thyroid, dental, echo, breast cancer, and skin cancer screening, there were negative associations between low education level and living below the poverty line, and clinician adherence to some survivorship screening. This indicates the need for tailored interventions in local contexts to optimize equitable long-term care. Unexpected findings related to screening were noted related to internet access, renting, and not having a car that are worth further exploration.
{"title":"Relationship between Social Drivers of Health and Clinician Adherence to Late Effects Screening Among Allogeneic HCT Survivors in the United States","authors":"Allison O. Taylor MD, MS , Sanghee Hong MD , Salene Jones PhD , Kevin Ng MS , Ted A. Gooley PhD , Neel Bhatt MBBS, MPH , Elizabeth M. Hellewell BS , Anthony D Sung MD , Nausheen Ahmed MD , Cherie Morey NP , Sarah Fitzmaurice NP , Vanessa E Kennedy MD , Michelle Lauer PA-C, MPH , Ami J. Shah MD , Andrew D. Trunk MD , Betty K. Hamilton MD , Akshay Sharma MBBS, MSc , Zoey Phelps-Bergeron PA-C , LaQuisa C. Hill MD , Rawan Faramand MD , Catherine J. Lee MD, MS","doi":"10.1016/j.jtct.2025.12.042","DOIUrl":"10.1016/j.jtct.2025.12.042","url":null,"abstract":"<div><h3>Introduction</h3><div>Social drivers of health (SDOH) are associated with inequities in healthcare. We report the associations between SDOH on clinicians’ adherence to post HCT survivorship screening guidelines.</div></div><div><h3>Methods</h3><div>We conducted a retrospective, multi-center cohort study of HCT survivors from 22 US centers transplanted in 2016, disease free ≥ 3 years post HCT. Zip-code derived SDOH variables were obtained from the US Census (Table 1). Patient, disease and transplant characteristics, and late effects screening (breast, cervical, skin, DEXA, vitamin D, HgbA1c, fasting glucose, echo, renal, lipid, thyroid and dental) were abstracted from the EMR. Clinician adherence was defined as order/test completion 11 months-2 yrs post HCT. Logistic regression evaluated the relationship between SDOH and clinician adherence. SDOH factors were modeled as continuous linear variables, with the corresponding odds ratio (OR) presented for each 10% proportional increase in the SDOH factor.</div></div><div><h3>Results</h3><div>Of 500 pts [≤ 39 yrs (n=212); > 39 yrs (n=288)], SDOH variables were available for 374 pts. Median age at HCT was 47 yrs (interquartile range/IQR 21-60). 58% were male, 83% were White and 12% were Hispanic (Table 2).</div><div>Decreased cervical cancer screening was associated with less than a high school diploma (0.29, 0.09-0.95, p=0.04). Less DEXA testing occurred with increased internet access (0.86, 0.76-0.98, p=0.03) while renting increased screening (1.12,1.02-1.32, p=0.03). Vitamin D screening increased with increase in supplemental security income/SSI (2.63, 1.20-5.80, p=0.02) and having no cars (1.67, 1.07-2.59, p=0.02). Fasting glucose screening was associated with direct purchase insurance (DPI) (1.69,1.03-2.77, p=0.04) and renting (1.21,1.04-1.41, p=0.02) while increased internet access decreased screening (0.83, 0.71-0.96, p=0.02). Increased lipid screening was associated with DPI (2.33, 1.42-3.81, p<0.01) but decreased in pts below the poverty line (0.71, 0.53-0.94 p=0.02) and with less than a high school diploma (0.71, 0.55-0.91, p=0.01). Renal screening correlated with increase in SSI (3.17, 1.31-7.66, p=0.01), Medicaid enrollment (1.37, 1.08-1.73, p=0.01), and having no cars (1.75,1.07-2.88 p=0.03).</div></div><div><h3>Conclusion</h3><div>While SDOH were not statistically significantly associated with clinician adherence to HgbA1c, thyroid, dental, echo, breast cancer, and skin cancer screening, there were negative associations between low education level and living below the poverty line, and clinician adherence to some survivorship screening. This indicates the need for tailored interventions in local contexts to optimize equitable long-term care. Unexpected findings related to screening were noted related to internet access, renting, and not having a car that are worth further exploration.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S24-S25"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/S2666-6367(25)02658-2
{"title":"Masthead (Purpose and Scope)","authors":"","doi":"10.1016/S2666-6367(25)02658-2","DOIUrl":"10.1016/S2666-6367(25)02658-2","url":null,"abstract":"","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages A1-A2"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.018
Heather J. Landau MD , Shahzad Raza MD , Aaron Rosenberg MD , Jeffrey Zonder MD , Raymond Comenzo MD , Vaishali Sanchorawala MD , Michaela Liedtke MD , Amandeep Godara MD , Jonathan L. Kaufman MD , Michael Rosenzweig MD , Charlotte F.M. Hughes MD , Eugene Brailovski MD , Hamza Hashmi MD , Mehrdad Abedi MD , Sham Mailankody MBBS , Jae H Park MD , David Marks MBBS, Phd , Sridevi Rajeeve MD , Jennifer Liu MD
<div><div>No FDA approved drugs exist for relapsed/refractory (RR) AL Amyloidosis. CAR-T is a novel approach. We report safety and efficacy from the first 23 pts in NEXICART-2, the first U.S. clinical trial of any CAR-T in RR AL Amyloidosis.</div><div>NEXICART-2 (NCT06097832) is a single-arm, multi-site U.S. Phase 1/2 trial of autologous BCMA-targeted CAR-T NXC-201 in RR AL Amyloidosis. It will enroll 40 pts. Pts have been exposed to bortezomib and anti-CD-38 antibody with persistent or relapsed disease with measurable disease (dFLC >5mg/dl or dFLC >2mg/dl with abnormal k:l ratio, or M-spike >0.5g/dl). LD was Flu/Cy. Primary endpoint is complete hematologic response (CR) (Palladini 2012, 2020, 2021). Cardiac, renal and hepatic responses were assessed by consensus criteria (Comenzo 2012; Palladini 2014).</div><div>23 pts (13 F, 10 M), median (med) age 66 yrs (range: 49 – 82) included. Med follow-up 168 days (range 63 – 463). Med prior lines 4 (range: 1 - 12); 12 (52%) prior stem cell transplant. Med dFLC 5.7 mg/dl (range: 2.0 – 31.0). Med NT-proBNP 323 ng/L (range: 61 - 2,017). 61% (14/23) cardiac disease (Diagnosis: Mayo stage I, II, IIIa, IIIb N=1,7,5,1; Enrollment: I, II, IIIa N=5,6,3, respectively). NYHA was I (N=6) and II (N=8). 30% (7/23) kidney disease, med 3g/24h (range 2 – 10g) proteinuria.</div><div>3, 20 pts received 150, 450 million CAR+T cells, respectively. Grade 1/2 (N=13/5) cytokine release syndrome (CRS) in 18 pts. CRS onset day 1/2/3 (N=13/2/3), med duration 1 day (range: 1-5). No ICANs or neurotoxicity of any kind was observed. Adverse events included neutropenia (grade 2/3/4 (N=2/10/10). 1 pt with pre-existing stage 4 chronic kidney disease prior to enrollment died 6 months after dosing due to dialysis catheter infection (deemed unrelated to drug). 3 pts with ≥ grade 3 infections, 1 grade 3 febrile neutropenia (4 days); 2 with pre-existing atrial fibrillation had transient arrythmias responsive to beta-blockers. No other cardiac toxicity or decompensation.</div><div>96% pts (22/23) normalized pathologic disease markers (involved FLC or M-spike) after NXC-201, med 7 days (range: 7 – 53), all with reduction of dFLC to <1 mg/dL. 17/20 MRD negative in bone marrow at day 25 (flow cytometry or clonoSEQ 10<sup>-5</sup> or 10<sup>-6</sup> sensitivity). MRD not yet available for 3 pts. 4 pts had a cardiac organ response and 2 improved NYHA from II to I. 2 and 1 pt had renal, liver organ responses, respectively. 1 pt with pre-existing stage 4 CKD prior to enrollment had renal progression; no cardiac progressions. As of the data cutoff, 20/23 pts treated with NXC-201 are in VGPR/CR, 3 PR/low dFLC PR; no hematologic progressions. All pts with >1 year follow-up (N = 3) remain in CR. Updated results will be communicated at presentation.</div><div>In the first 23-pt U.S. CAR-T trial in RR AL Amyloidosis, we show NXC-201 can be given safely and results in rapid and deep hematologic responses in all pts treated. The novel anti-BC
{"title":"First 23-Patient Safety and Efficacy Data from Nexicart-2, the First U.S. Trial of CAR-T in R/R Light Chain (AL) Amyloidosis, Nxc-201","authors":"Heather J. Landau MD , Shahzad Raza MD , Aaron Rosenberg MD , Jeffrey Zonder MD , Raymond Comenzo MD , Vaishali Sanchorawala MD , Michaela Liedtke MD , Amandeep Godara MD , Jonathan L. Kaufman MD , Michael Rosenzweig MD , Charlotte F.M. Hughes MD , Eugene Brailovski MD , Hamza Hashmi MD , Mehrdad Abedi MD , Sham Mailankody MBBS , Jae H Park MD , David Marks MBBS, Phd , Sridevi Rajeeve MD , Jennifer Liu MD","doi":"10.1016/j.jtct.2025.12.018","DOIUrl":"10.1016/j.jtct.2025.12.018","url":null,"abstract":"<div><div>No FDA approved drugs exist for relapsed/refractory (RR) AL Amyloidosis. CAR-T is a novel approach. We report safety and efficacy from the first 23 pts in NEXICART-2, the first U.S. clinical trial of any CAR-T in RR AL Amyloidosis.</div><div>NEXICART-2 (NCT06097832) is a single-arm, multi-site U.S. Phase 1/2 trial of autologous BCMA-targeted CAR-T NXC-201 in RR AL Amyloidosis. It will enroll 40 pts. Pts have been exposed to bortezomib and anti-CD-38 antibody with persistent or relapsed disease with measurable disease (dFLC >5mg/dl or dFLC >2mg/dl with abnormal k:l ratio, or M-spike >0.5g/dl). LD was Flu/Cy. Primary endpoint is complete hematologic response (CR) (Palladini 2012, 2020, 2021). Cardiac, renal and hepatic responses were assessed by consensus criteria (Comenzo 2012; Palladini 2014).</div><div>23 pts (13 F, 10 M), median (med) age 66 yrs (range: 49 – 82) included. Med follow-up 168 days (range 63 – 463). Med prior lines 4 (range: 1 - 12); 12 (52%) prior stem cell transplant. Med dFLC 5.7 mg/dl (range: 2.0 – 31.0). Med NT-proBNP 323 ng/L (range: 61 - 2,017). 61% (14/23) cardiac disease (Diagnosis: Mayo stage I, II, IIIa, IIIb N=1,7,5,1; Enrollment: I, II, IIIa N=5,6,3, respectively). NYHA was I (N=6) and II (N=8). 30% (7/23) kidney disease, med 3g/24h (range 2 – 10g) proteinuria.</div><div>3, 20 pts received 150, 450 million CAR+T cells, respectively. Grade 1/2 (N=13/5) cytokine release syndrome (CRS) in 18 pts. CRS onset day 1/2/3 (N=13/2/3), med duration 1 day (range: 1-5). No ICANs or neurotoxicity of any kind was observed. Adverse events included neutropenia (grade 2/3/4 (N=2/10/10). 1 pt with pre-existing stage 4 chronic kidney disease prior to enrollment died 6 months after dosing due to dialysis catheter infection (deemed unrelated to drug). 3 pts with ≥ grade 3 infections, 1 grade 3 febrile neutropenia (4 days); 2 with pre-existing atrial fibrillation had transient arrythmias responsive to beta-blockers. No other cardiac toxicity or decompensation.</div><div>96% pts (22/23) normalized pathologic disease markers (involved FLC or M-spike) after NXC-201, med 7 days (range: 7 – 53), all with reduction of dFLC to <1 mg/dL. 17/20 MRD negative in bone marrow at day 25 (flow cytometry or clonoSEQ 10<sup>-5</sup> or 10<sup>-6</sup> sensitivity). MRD not yet available for 3 pts. 4 pts had a cardiac organ response and 2 improved NYHA from II to I. 2 and 1 pt had renal, liver organ responses, respectively. 1 pt with pre-existing stage 4 CKD prior to enrollment had renal progression; no cardiac progressions. As of the data cutoff, 20/23 pts treated with NXC-201 are in VGPR/CR, 3 PR/low dFLC PR; no hematologic progressions. All pts with >1 year follow-up (N = 3) remain in CR. Updated results will be communicated at presentation.</div><div>In the first 23-pt U.S. CAR-T trial in RR AL Amyloidosis, we show NXC-201 can be given safely and results in rapid and deep hematologic responses in all pts treated. The novel anti-BC","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S4"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.019
Jennifer Meyer Feigin B.S. , Omar Gutierrez-Ruiz Ph.D. , Carli M. Stewart Ph.D. , Brooke Kimball B.S. , Kun Yun M.S., Ph.D. , Mehrdad Hefazi M.D. , Claudia Manriquez-Roman M.S., Ph.D. , Wannakorn Khopanlert M.D., Ph.D. , Long K. Mai B.S. , Truc N. Huynh M.S. , Sophia Y. Goldberg A.B. , Grace E. DeFranco B.S. , Ismail Can Ph.D. , Ateka Saleh B.Pharm. , Olivia L. Sirpilla Ph.D. , Dominic Skeele B.S. , Ekene J. Ogbodo Ph.D. , Hong Xia M.D. , P. Leif Bergsagel M.D. , Yi Lin MD, PhD , Saad S. Kenderian M.D.
<div><div>Chimeric antigen receptor T (CART) cell therapies targeting B cell maturation antigen (BCMA) have emerged as promising treatments for multiple myeloma (MM). However, most patients relapse within 3 years. The MM tumor microenvironment (TME) is highly immunosuppressive with an abundance of bone marrow (BM) cancer-associated fibroblasts (CAFs). However, BM-CAF interactions with BCMA-CART cells, cancer cells, and other TME components in MM remain unknown.</div><div>To elucidate the nature of BM-CAF crosstalk with CART cells and other MM TME cells, we performed single-cell RNA sequencing of baseline BM aspirates from BCMA-CART responders (R, n=6) and non-responders (NR, n=6). NR BMs were enriched for inhibitory CAFs (iCAFs) that highly express fibroblast activation protein (FAP). Spatial analyses of BM cells showed greater iCAF-iCAF and iCAF-inhibitory macrophage interactions in NR. These findings indicate that FAP<sup>+</sup> iCAFs are abundant in NR BMs and exhibit significant interactions with suppressive macrophages.</div><div>To overcome CAF-mediated CART inhibition, we designed BCMA-CART cells capable of secreting molecules to target BM FAP<sup>+</sup> iCAFs and remodel the MM-TME (STriKEs). We designed two BCMA-CART-STriKE strategies: 1) a tri-specific composed of IL-15, anti-FAP, and anti-CD16 molecules to activate innate immune cells to kill CAFs and 2) bi-specific anti-FAP, anti-SIRPα molecules linked to an antibody Fc region (Fc fusion) targeting the CD47/SIRPα axis to induce phagocytosis of FAP<sup>+</sup> iCAFs. We hypothesized that BCMA-CART-STriKEs would surmount CAF-mediated immunosuppression without toxicity.</div><div>After confirming <em>in vitro</em> potency, we assessed BCMA-CART-STriKE efficacy <em>in vivo</em>. NOD-SCID-γ-/- (NSG) mice received patient-derived (pd) BM-CAFs and luciferase<sup>+</sup> OPM2 cells via IV injection (1 × 10<sup>6</sup> each.) After confirming engraftment and randomizing (via bioluminescence imaging), mice received IV treatment with 1 × 10<sup>6</sup> BCMA-CART-STriKEs (or controls) and 5 × 10<sup>5</sup> donor-matched macrophages. BCMA-CART-STriKE-treated mice achieved total tumor clearance. Treatment with BCMA-CART cells secreting IL-15 led to lethal weight loss despite tumor clearance while BCMA-CART cells secreting Fc fusions targeting only FAP or SIRPα failed to eradicate tumors.</div><div>Lastly, we assessed the potential toxicity of BCMA-CART-STriKEs in humanized mice engrafted with OPM2 cells and pd-BM-CAFs (1 × 10<sup>6</sup> each). T cells constitutively expressing BCMA and FAP CARs (BCMA-FAP CART) served as a control. BCMA-FAP CART treatment resulted in significant toxicity and weight loss while BCMA-CART-STriKEs did not (p<0.01).</div><div>In sum, we have identified iCAF interactions with suppressive immune cells as key contributors to BCMA-CART cell failure and designed novel BCMA-CART-STriKEs that overcome this failure in MM preclinical models. These findings support the tran
{"title":"Remodeling the Multiple Myeloma Bone Marrow Microenvironment with CART Cells to Overcome Resistance","authors":"Jennifer Meyer Feigin B.S. , Omar Gutierrez-Ruiz Ph.D. , Carli M. Stewart Ph.D. , Brooke Kimball B.S. , Kun Yun M.S., Ph.D. , Mehrdad Hefazi M.D. , Claudia Manriquez-Roman M.S., Ph.D. , Wannakorn Khopanlert M.D., Ph.D. , Long K. Mai B.S. , Truc N. Huynh M.S. , Sophia Y. Goldberg A.B. , Grace E. DeFranco B.S. , Ismail Can Ph.D. , Ateka Saleh B.Pharm. , Olivia L. Sirpilla Ph.D. , Dominic Skeele B.S. , Ekene J. Ogbodo Ph.D. , Hong Xia M.D. , P. Leif Bergsagel M.D. , Yi Lin MD, PhD , Saad S. Kenderian M.D.","doi":"10.1016/j.jtct.2025.12.019","DOIUrl":"10.1016/j.jtct.2025.12.019","url":null,"abstract":"<div><div>Chimeric antigen receptor T (CART) cell therapies targeting B cell maturation antigen (BCMA) have emerged as promising treatments for multiple myeloma (MM). However, most patients relapse within 3 years. The MM tumor microenvironment (TME) is highly immunosuppressive with an abundance of bone marrow (BM) cancer-associated fibroblasts (CAFs). However, BM-CAF interactions with BCMA-CART cells, cancer cells, and other TME components in MM remain unknown.</div><div>To elucidate the nature of BM-CAF crosstalk with CART cells and other MM TME cells, we performed single-cell RNA sequencing of baseline BM aspirates from BCMA-CART responders (R, n=6) and non-responders (NR, n=6). NR BMs were enriched for inhibitory CAFs (iCAFs) that highly express fibroblast activation protein (FAP). Spatial analyses of BM cells showed greater iCAF-iCAF and iCAF-inhibitory macrophage interactions in NR. These findings indicate that FAP<sup>+</sup> iCAFs are abundant in NR BMs and exhibit significant interactions with suppressive macrophages.</div><div>To overcome CAF-mediated CART inhibition, we designed BCMA-CART cells capable of secreting molecules to target BM FAP<sup>+</sup> iCAFs and remodel the MM-TME (STriKEs). We designed two BCMA-CART-STriKE strategies: 1) a tri-specific composed of IL-15, anti-FAP, and anti-CD16 molecules to activate innate immune cells to kill CAFs and 2) bi-specific anti-FAP, anti-SIRPα molecules linked to an antibody Fc region (Fc fusion) targeting the CD47/SIRPα axis to induce phagocytosis of FAP<sup>+</sup> iCAFs. We hypothesized that BCMA-CART-STriKEs would surmount CAF-mediated immunosuppression without toxicity.</div><div>After confirming <em>in vitro</em> potency, we assessed BCMA-CART-STriKE efficacy <em>in vivo</em>. NOD-SCID-γ-/- (NSG) mice received patient-derived (pd) BM-CAFs and luciferase<sup>+</sup> OPM2 cells via IV injection (1 × 10<sup>6</sup> each.) After confirming engraftment and randomizing (via bioluminescence imaging), mice received IV treatment with 1 × 10<sup>6</sup> BCMA-CART-STriKEs (or controls) and 5 × 10<sup>5</sup> donor-matched macrophages. BCMA-CART-STriKE-treated mice achieved total tumor clearance. Treatment with BCMA-CART cells secreting IL-15 led to lethal weight loss despite tumor clearance while BCMA-CART cells secreting Fc fusions targeting only FAP or SIRPα failed to eradicate tumors.</div><div>Lastly, we assessed the potential toxicity of BCMA-CART-STriKEs in humanized mice engrafted with OPM2 cells and pd-BM-CAFs (1 × 10<sup>6</sup> each). T cells constitutively expressing BCMA and FAP CARs (BCMA-FAP CART) served as a control. BCMA-FAP CART treatment resulted in significant toxicity and weight loss while BCMA-CART-STriKEs did not (p<0.01).</div><div>In sum, we have identified iCAF interactions with suppressive immune cells as key contributors to BCMA-CART cell failure and designed novel BCMA-CART-STriKEs that overcome this failure in MM preclinical models. These findings support the tran","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S4-S5"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.087
Maryam Rafati MD, PhD , Filip Pirsl PhD , Hormuzd A. Katki PhD , Dongjing Wu MS , Wen Luo PhD , Kristine Jones BSc , Weiyin Zhou MS , Jianxin Shi PhD , Stephen R. Spellman MBS , Yung-Tsi Bolon PhD , Stephanie J. Lee MD, MPH , H. Joachim Deeg MD , Vikas Gupta MD , Wael Saber WS , Shahinaz M. Gadalla MD, PhD
<div><h3>Background</h3><div>The prognostic impact of the molecular genetic landscape of myelofibrosis (MF) on hematopoietic cell transplantation (HCT) outcomes remains unclear. This study evaluates gene-specific associations with HCT outcomes in MF patients, overall and by driver mutation status.</div></div><div><h3>Methods</h3><div>We performed deep sequencing (mean depth 664x) of 95 myeloid genes in DNA from pre-HCT blood samples of 930 patients with primary or secondary MF who underwent HCT between 2000 and 2016, with clinical data and pre-HCT blood samples available at CIBMTR®. Somatic variants were called using Mutect2 and germline variants were filtered out using a panel of normals constructed from 989 age- and sex-matched controls, and the Pan-Cancer Analysis of Whole Genomes (PCAWG). Only pathogenic/likely pathogenic (PLP) variants, defined according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, were included. Cox proportional hazards models were used to assess overall survival (OS) with final models adjusted for patient age and sex, DIPSS, donor-recipient CMV match, donor type, and year of transplant. Genes detected in ≥5% of patients (N ≥47) were included in OS analysis.</div></div><div><h3>Results</h3><div>Driver mutations were detected in 81.7% of the patients, with <em>JAK2</em> the most common (57.3%) followed by <em>CALR</em> (19.6%), and <em>MPL</em> (6%), leaving 170 patients (18.3%) triple-negative (TN). Other common mutations included <em>ASXL1 (312, 33.5%), U2AF1</em> (133, 14.3%), <em>TET2</em> (132, 14.2%), <em>SRSF2</em> (116, 12.5%), and <em>TP53</em> (78, 8.4%) (Figure 1). Compared to <em>JAK2</em>+ patients, TN patients had inferior OS (HR=1.54; p<0.001), while no significant OS differences were observed for <em>CALR+</em> (HR=0.81; p=0.11) or <em>MPL+</em> (HR=0.70; p=0.13) patients (Figure 2A). Mutations in high molecular risk (HMR) genes combined <em>(ASXL1, EZH2, IDH1/2, SRSF2, U2AF1, CBL, KRAS, NRAS)</em> were not associated with survival (HR=0.90; p=0.30; Figure 2B). PLP variants in <em>TP53</em> were linked to inferior OS across patients (HR=2.68; p<0.001; Figure 2C), increasing relapse/disease progression risk in <em>CALR</em>+ (HR=2.70; p=0.03) and possibly TN (HR=2.00; p=0.14), and transplant-related mortality (TRM) risk in <em>JAK2</em>+ patients (HR=1.89; p=0.008). In TN patients, the adverse prognosis was primarily driven by <em>TET2</em> mutations (HR=2.16; p=0.007), specifically associated with relapse (HR = 2.22; p = 0.02). <em>ASXL1</em> mutations increased post-HCT mortality only in <em>MPL</em>+ patients (HR = 3.78; p = 0.01), mainly due to excess TRM (HR = 4.84; p = 0.05).</div></div><div><h3>Conclusions</h3><div><em>TP53</em> mutations are strong predictors of poor outcomes across MF patients, whereas <em>TET2</em> and <em>ASXL1</em> mutations confer prognostic value only in TN and <em>MPL</em>+ patients respectively. The abse
{"title":"Genetic Predictors of Hematopoietic Cell Transplantation Outcomes in Patients with Myelofibrosis","authors":"Maryam Rafati MD, PhD , Filip Pirsl PhD , Hormuzd A. Katki PhD , Dongjing Wu MS , Wen Luo PhD , Kristine Jones BSc , Weiyin Zhou MS , Jianxin Shi PhD , Stephen R. Spellman MBS , Yung-Tsi Bolon PhD , Stephanie J. Lee MD, MPH , H. Joachim Deeg MD , Vikas Gupta MD , Wael Saber WS , Shahinaz M. Gadalla MD, PhD","doi":"10.1016/j.jtct.2025.12.087","DOIUrl":"10.1016/j.jtct.2025.12.087","url":null,"abstract":"<div><h3>Background</h3><div>The prognostic impact of the molecular genetic landscape of myelofibrosis (MF) on hematopoietic cell transplantation (HCT) outcomes remains unclear. This study evaluates gene-specific associations with HCT outcomes in MF patients, overall and by driver mutation status.</div></div><div><h3>Methods</h3><div>We performed deep sequencing (mean depth 664x) of 95 myeloid genes in DNA from pre-HCT blood samples of 930 patients with primary or secondary MF who underwent HCT between 2000 and 2016, with clinical data and pre-HCT blood samples available at CIBMTR®. Somatic variants were called using Mutect2 and germline variants were filtered out using a panel of normals constructed from 989 age- and sex-matched controls, and the Pan-Cancer Analysis of Whole Genomes (PCAWG). Only pathogenic/likely pathogenic (PLP) variants, defined according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, were included. Cox proportional hazards models were used to assess overall survival (OS) with final models adjusted for patient age and sex, DIPSS, donor-recipient CMV match, donor type, and year of transplant. Genes detected in ≥5% of patients (N ≥47) were included in OS analysis.</div></div><div><h3>Results</h3><div>Driver mutations were detected in 81.7% of the patients, with <em>JAK2</em> the most common (57.3%) followed by <em>CALR</em> (19.6%), and <em>MPL</em> (6%), leaving 170 patients (18.3%) triple-negative (TN). Other common mutations included <em>ASXL1 (312, 33.5%), U2AF1</em> (133, 14.3%), <em>TET2</em> (132, 14.2%), <em>SRSF2</em> (116, 12.5%), and <em>TP53</em> (78, 8.4%) (Figure 1). Compared to <em>JAK2</em>+ patients, TN patients had inferior OS (HR=1.54; p<0.001), while no significant OS differences were observed for <em>CALR+</em> (HR=0.81; p=0.11) or <em>MPL+</em> (HR=0.70; p=0.13) patients (Figure 2A). Mutations in high molecular risk (HMR) genes combined <em>(ASXL1, EZH2, IDH1/2, SRSF2, U2AF1, CBL, KRAS, NRAS)</em> were not associated with survival (HR=0.90; p=0.30; Figure 2B). PLP variants in <em>TP53</em> were linked to inferior OS across patients (HR=2.68; p<0.001; Figure 2C), increasing relapse/disease progression risk in <em>CALR</em>+ (HR=2.70; p=0.03) and possibly TN (HR=2.00; p=0.14), and transplant-related mortality (TRM) risk in <em>JAK2</em>+ patients (HR=1.89; p=0.008). In TN patients, the adverse prognosis was primarily driven by <em>TET2</em> mutations (HR=2.16; p=0.007), specifically associated with relapse (HR = 2.22; p = 0.02). <em>ASXL1</em> mutations increased post-HCT mortality only in <em>MPL</em>+ patients (HR = 3.78; p = 0.01), mainly due to excess TRM (HR = 4.84; p = 0.05).</div></div><div><h3>Conclusions</h3><div><em>TP53</em> mutations are strong predictors of poor outcomes across MF patients, whereas <em>TET2</em> and <em>ASXL1</em> mutations confer prognostic value only in TN and <em>MPL</em>+ patients respectively. The abse","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S57-S58"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.090
Ashley M. Nelson PhD , Heather SL Jim PhD , Richard Newcomb MD , Jessica Giorgio B.A. , Ally M. Wood B.S. , Dustin Rabideau phD , Lara Traeger PhD , Yi-Bin Chen MD , Zachariah DeFilipp MD , Stephanie J. Lee MD, MPH , Hans Knoop PhD , Joseph A. Greer PhD , Areej El-Jawahri MD
Background
Fatigue is a common and impairing symptom following blood and marrow transplantation (BMT), with more than one-third of BMT recipients experiencing clinically significant fatigue in the years following transplant.
Methods
We conducted a single-center pilot randomized trial of a cognitive-behavioral intervention to address fatigue (Energize-BMT; n=28) compared to enhanced usual care (n=32) among allogeneic and autologous BMT recipients who were at least six months post-transplant and experiencing moderate to severe fatigue (severity rating ≥4; 0-10 scale). Energize-BMT participants received up to ten sessions with a study counselor via a videoconferencing platform over twelve weeks, facilitated with a workbook. All participants completed surveys of fatigue (FACIT-F), quality of life (FACT-BMT), and mood (PROMIS Depression and Anxiety) before randomization and at 3- and 5-months post-randomization. The primary endpoint was feasibility, defined as having ≥60% of approached patients enroll, ≥70% intervention patients complete at least seven of ten Energize-BMT sessions, and ≥70% of all participants complete follow-up surveys. We also explored effects on fatigue using analysis of covariance and Cohen's d estimates of effect size at 3-months.
Results
From 07/2024 to 04/2025, we consented 61.3% (n=68/111) and enrolled 54.1% (n=60/111) of eligible patients (median age =62 years, range: 30-78 years; n=32 female; n=56 allogeneic BMT; n=28 chronic graft-versus-host disease). Of those randomized to receive Energize-BMT, 78.6% (n=22/28) completed at least seven of ten sessions, with the remaining patients completing four to six sessions (n=3) or no sessions (n=3). Of enrolled participants, 86.7% (n=52/60) completed the 3-month follow-up survey. Patients randomized to Energize-BMT reported improved fatigue at 3-months compared to those who received usual care (adjusted means, 43.2 vs 33.0, p<.001; d=1.10).
Conclusion
Energize-BMT, a remotely delivered cognitive-behavioral intervention, was feasible and promising for improving clinically significant fatigue post-transplant. A larger randomized clinical trial is needed to evaluate intervention efficacy.
{"title":"Cognitive Behavioral Intervention to Reduce Persistent Fatigue Following Blood and Marrow Transplantation: Results from a Pilot Randomized Clinical Trial","authors":"Ashley M. Nelson PhD , Heather SL Jim PhD , Richard Newcomb MD , Jessica Giorgio B.A. , Ally M. Wood B.S. , Dustin Rabideau phD , Lara Traeger PhD , Yi-Bin Chen MD , Zachariah DeFilipp MD , Stephanie J. Lee MD, MPH , Hans Knoop PhD , Joseph A. Greer PhD , Areej El-Jawahri MD","doi":"10.1016/j.jtct.2025.12.090","DOIUrl":"10.1016/j.jtct.2025.12.090","url":null,"abstract":"<div><h3>Background</h3><div>Fatigue is a common and impairing symptom following blood and marrow transplantation (BMT), with more than one-third of BMT recipients experiencing clinically significant fatigue in the years following transplant.</div></div><div><h3>Methods</h3><div>We conducted a single-center pilot randomized trial of a cognitive-behavioral intervention to address fatigue (Energize-BMT; n=28) compared to enhanced usual care (n=32) among allogeneic and autologous BMT recipients who were at least six months post-transplant and experiencing moderate to severe fatigue (severity rating ≥4; 0-10 scale). Energize-BMT participants received up to ten sessions with a study counselor via a videoconferencing platform over twelve weeks, facilitated with a workbook. All participants completed surveys of fatigue (FACIT-F), quality of life (FACT-BMT), and mood (PROMIS Depression and Anxiety) before randomization and at 3- and 5-months post-randomization. The primary endpoint was feasibility, defined as having ≥60% of approached patients enroll, ≥70% intervention patients complete at least seven of ten Energize-BMT sessions, and ≥70% of all participants complete follow-up surveys. We also explored effects on fatigue using analysis of covariance and Cohen's d estimates of effect size at 3-months.</div></div><div><h3>Results</h3><div>From 07/2024 to 04/2025, we consented 61.3% (n=68/111) and enrolled 54.1% (n=60/111) of eligible patients (median age =62 years, range: 30-78 years; n=32 female; n=56 allogeneic BMT; n=28 chronic graft-versus-host disease). Of those randomized to receive Energize-BMT, 78.6% (n=22/28) completed at least seven of ten sessions, with the remaining patients completing four to six sessions (n=3) or no sessions (n=3). Of enrolled participants, 86.7% (n=52/60) completed the 3-month follow-up survey. Patients randomized to Energize-BMT reported improved fatigue at 3-months compared to those who received usual care (adjusted means, 43.2 vs 33.0, p<.001; d=1.10).</div></div><div><h3>Conclusion</h3><div>Energize-BMT, a remotely delivered cognitive-behavioral intervention, was feasible and promising for improving clinically significant fatigue post-transplant. A larger randomized clinical trial is needed to evaluate intervention efficacy.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Pages S59-S60"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.103
Avijeet Kumar Mishra MBBS , Lucille Langenberg BS , Lauren Strecker BS , Qiuhong Zhao MS , Sonata Jodele MD , Dr. Anthony Sabulski MD , Sumithira Vasu MBBS , Nelli Bejanyan MD , Theresa E. Hahn PhD , Stella M. Davies MBBS, PhD, MRCP
<div><h3>Background</h3><div>TA-TMA complicates up to a third of pediatric hematopoietic stem cell transplants (HSCT). The MIDAS consortium, the first prospective observational study of TA-TMA in adult HSCT recipients across three U.S. centers, reported a similar incidence in adults, with 20% classified as severe. While about 70% of pediatric patients respond to complement blockade, adults show a suboptimal response, suggesting a distinct pathophysiology from the rapid complement activation in children. We hypothesized that pre-existing endothelial activation in adults is a consequence of inflammation associated with accelerated aging and increases the risk of TA-TMA in adults.</div></div><div><h3>Objective</h3><div>To measure soluble urokinase plasminogen activator receptor (suPAR) and monocyte chemoattractant protein-1 (MCP1), proteins associated with chronic inflammation and accelerated aging, termed senescence-associated secretory phenotype (SASP) proteins.</div></div><div><h3>Method</h3><div>Serum suPAR and MCP1 were measured by ELISA in 220 adult MIDAS and 125 pediatric HSCT patients at pre-defined timepoints. Logistic regression evaluated biomarker associations with TA-TMA, with results reported as odds ratio per two-fold increase with 95% confidence intervals; statistical significance was set at p<0.01.</div></div><div><h3>Result</h3><div>Baseline characteristics are shown in Figures 1A and 1B. In the MIDAS adult cohort, higher suPAR was associated with higher odds of TA-TMA at all timepoints, including pre-transplant (Fig. 2A). A higher MCP1 level was similarly associated with increased risk of TA-TMA early in the transplant process, at days 7 and 14 (Fig. 2B). In contrast, in the pediatric cohort, suPAR (Fig. 2C) was associated with TA-TMA only at day 28, coinciding with the median time of diagnosis in the pediatric cohort (29 days, 0–526). MCP1 was not associated with TA-TMA at any timepoint (Fig. 2D). In the pediatric cohort, both suPAR and MCP1 were significant on day 28 on association analysis; however, only suPAR remained significant in the landmark analysis.</div></div><div><h3>Discussion</h3><div>In adults, suPAR and MCP1 levels were significantly elevated prior to TA-TMA onset (median day of TA-TMA onset 14.5 days) and, in the case of suPAR, also prior to the start of transplant. In contrast, in children, elevation of suPAR occurred later, coinciding with median onset of TA-TMA at day 29. The limited response of adult TA-TMA to complement inhibition, combined with elevations in SASP-associated biomarkers shown here, points to a mechanistically distinct, complement-independent pathophysiology. In children, rapid complement activation likely drives later biomarker elevation (Fig. 3A), while in adults, persistent inflammation and senescence-related processes may contribute to pre-existing inflammation and rapid occurrence of TA-TMA, earlier than is seen in children (Fig. 3B). Further studies are urgently needed to elucidate adul
{"title":"Transplant Associated Thrombotic Microangiopathy (TA-TMA) Is Mechanistically Different in Adults and Children- a MIDAS (Microangiopathy, Endothelial Damage in Adults undergoing Stem cell transplantation) Consortium Study","authors":"Avijeet Kumar Mishra MBBS , Lucille Langenberg BS , Lauren Strecker BS , Qiuhong Zhao MS , Sonata Jodele MD , Dr. Anthony Sabulski MD , Sumithira Vasu MBBS , Nelli Bejanyan MD , Theresa E. Hahn PhD , Stella M. Davies MBBS, PhD, MRCP","doi":"10.1016/j.jtct.2025.12.103","DOIUrl":"10.1016/j.jtct.2025.12.103","url":null,"abstract":"<div><h3>Background</h3><div>TA-TMA complicates up to a third of pediatric hematopoietic stem cell transplants (HSCT). The MIDAS consortium, the first prospective observational study of TA-TMA in adult HSCT recipients across three U.S. centers, reported a similar incidence in adults, with 20% classified as severe. While about 70% of pediatric patients respond to complement blockade, adults show a suboptimal response, suggesting a distinct pathophysiology from the rapid complement activation in children. We hypothesized that pre-existing endothelial activation in adults is a consequence of inflammation associated with accelerated aging and increases the risk of TA-TMA in adults.</div></div><div><h3>Objective</h3><div>To measure soluble urokinase plasminogen activator receptor (suPAR) and monocyte chemoattractant protein-1 (MCP1), proteins associated with chronic inflammation and accelerated aging, termed senescence-associated secretory phenotype (SASP) proteins.</div></div><div><h3>Method</h3><div>Serum suPAR and MCP1 were measured by ELISA in 220 adult MIDAS and 125 pediatric HSCT patients at pre-defined timepoints. Logistic regression evaluated biomarker associations with TA-TMA, with results reported as odds ratio per two-fold increase with 95% confidence intervals; statistical significance was set at p<0.01.</div></div><div><h3>Result</h3><div>Baseline characteristics are shown in Figures 1A and 1B. In the MIDAS adult cohort, higher suPAR was associated with higher odds of TA-TMA at all timepoints, including pre-transplant (Fig. 2A). A higher MCP1 level was similarly associated with increased risk of TA-TMA early in the transplant process, at days 7 and 14 (Fig. 2B). In contrast, in the pediatric cohort, suPAR (Fig. 2C) was associated with TA-TMA only at day 28, coinciding with the median time of diagnosis in the pediatric cohort (29 days, 0–526). MCP1 was not associated with TA-TMA at any timepoint (Fig. 2D). In the pediatric cohort, both suPAR and MCP1 were significant on day 28 on association analysis; however, only suPAR remained significant in the landmark analysis.</div></div><div><h3>Discussion</h3><div>In adults, suPAR and MCP1 levels were significantly elevated prior to TA-TMA onset (median day of TA-TMA onset 14.5 days) and, in the case of suPAR, also prior to the start of transplant. In contrast, in children, elevation of suPAR occurred later, coinciding with median onset of TA-TMA at day 29. The limited response of adult TA-TMA to complement inhibition, combined with elevations in SASP-associated biomarkers shown here, points to a mechanistically distinct, complement-independent pathophysiology. In children, rapid complement activation likely drives later biomarker elevation (Fig. 3A), while in adults, persistent inflammation and senescence-related processes may contribute to pre-existing inflammation and rapid occurrence of TA-TMA, earlier than is seen in children (Fig. 3B). Further studies are urgently needed to elucidate adul","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S69"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jtct.2025.12.027
Kenneth Jin Chang Lim MBBS , Ricardo Daniel Parrondo MD , Saurabh Chhabra MD, MS , Katharine Dooley M.P.H , Andre De Menezes Silva Corraes , Darin Carabenciov MD , Morie Gertz MD , Lisa Hwa CNP , Haily Stephens PA-C , Prashant Kapoor MD , Melinda Tan MD , Taxiarchis Kourelis MD , Rahma Warsame MD , Joselle Cook MD , Moritz Binder MD, MPH , P. Leif Bergsagel M.D. , Udit Yadav MD , Julia Erin Wiedmeier-Nutor MD, MPH , Susan Geyer Ph.D , Saurabh S. Zanwar MBBS , Yi Lin MD, PhD
<div><h3>Introduction</h3><div>Cilta-cel is associated with a 10-15% risk of delayed neurotoxicity (DNT) with cranial nerve palsies (IEC-NP) and parkinsonism (IEC-PKS) seen at a rate of 10% and 1-4% respectively. It has been shown that high post-infusion peak absolute lymphocyte count (ALCpeak) of >3x10^9/L is associated with an increased risk of delayed neurotoxicity (Lim et al., ASCO 2025) whilst the risk was negligible (∼1%) below that threshold.</div></div><div><h3>Objectives</h3><div>We examined the outcome of cilta-cel treated Multiple Myeloma (MM) patients (pts) with high ALCpeak treated with prophylactic dexamethasone (PPX DEX) at Mayo Clinic since 12/2024.</div></div><div><h3>Methods</h3><div>Retrospective analysis of 102 pts (new cohort) treated with cilta-cel between 12/2024-05/2025 after the introduction of PPX DEX using an oral 10mg bid dose for at least three days in pts with high ALCpeak (>3x10^9/L). This is compared to 230 pts who received cilta-cel between 02/2022 -11/2024 (historical cohort) where PPX DEX was not used.</div></div><div><h3>Results</h3><div>No significant differences were seen in pre-infusion disease burden, rates of all/high-grade CRS or ICANS, IEC-HS and tocilizumub use in the new vs historical cohorts. The new cohort had a median follow-up of 3.6 months where high ALCpeak was observed in 49 (48%) pts of which DNT was observed in 11 (22%) pts: 3 (6%) IEC-PKS and 8 (16%) IEC-NP. DNT was observed in 1 (2%) pt with ALCpeak <3x10^9/L who developed IEC-NP. In the new cohort, 43 (42%) pts received DEX (34 PPX DEX and 9 treatment DEX). Among DEX-treated pts, DNT was observed in 8 (19%) pts; 2 (5%) IEC-PKS, 6 (14%) IEC-NP. DNT rates between pts receiving DEX for high ALCpeak were compared against the historical cohort with high ALCpeak (n=97). Estimated 90-day DNT by Kaplan-Meier method was (19% vs 21%; p=0.49): IEC-PKS (5% vs 7%; p=0.46) and IEC-NP (16% vs 13%; p=0.96). The use of DEX did not significantly reduce the risk of DNT (HR 0.76, 95% CI: 0.34-1.70), IEC-PKS (HR 0.57, 95% CI: 0.12-2.64) or IEC-NP (0.98, 95% CI: 0.37-2.55) vs the historical cohort.</div><div>ALC expansion over the first month post CAR-T infusion (area under the curve, AUC) was next assessed. No difference in median AUC was seen in pts receiving DEX vs the historical cohort with high ALCpeak (37 vs 44, p=0.13). Amongst pts receiving DEX, median AUC was not different between pts who developed DNT vs those who did not (71 vs 30, p=0.16)</div><div>Among pts with DNT, no differences were observed in the severity of presentation between pts who received PPX DEX vs DNT cases from the historical cohort. Two of 3 IEC-PKS had PPX DEX but presented with severe symptoms; non-responsive to methylprednisolone, intrathecal chemotherapy and high-dose cyclophosphamide. Both pts subsequently died from sepsis.</div></div><div><h3>Conclusion</h3><div>While ALCpeak >3x10^9/L predicts risk of DNT in pts treated with cilta-cel, the use of DEX neither reduc
{"title":"Investigating the Role of Dexamethasone Prophylaxis for the Risk Reduction of Immune Effector Cell Delayed Neurotoxicity in Cilta-Cel Treated Patients","authors":"Kenneth Jin Chang Lim MBBS , Ricardo Daniel Parrondo MD , Saurabh Chhabra MD, MS , Katharine Dooley M.P.H , Andre De Menezes Silva Corraes , Darin Carabenciov MD , Morie Gertz MD , Lisa Hwa CNP , Haily Stephens PA-C , Prashant Kapoor MD , Melinda Tan MD , Taxiarchis Kourelis MD , Rahma Warsame MD , Joselle Cook MD , Moritz Binder MD, MPH , P. Leif Bergsagel M.D. , Udit Yadav MD , Julia Erin Wiedmeier-Nutor MD, MPH , Susan Geyer Ph.D , Saurabh S. Zanwar MBBS , Yi Lin MD, PhD","doi":"10.1016/j.jtct.2025.12.027","DOIUrl":"10.1016/j.jtct.2025.12.027","url":null,"abstract":"<div><h3>Introduction</h3><div>Cilta-cel is associated with a 10-15% risk of delayed neurotoxicity (DNT) with cranial nerve palsies (IEC-NP) and parkinsonism (IEC-PKS) seen at a rate of 10% and 1-4% respectively. It has been shown that high post-infusion peak absolute lymphocyte count (ALCpeak) of >3x10^9/L is associated with an increased risk of delayed neurotoxicity (Lim et al., ASCO 2025) whilst the risk was negligible (∼1%) below that threshold.</div></div><div><h3>Objectives</h3><div>We examined the outcome of cilta-cel treated Multiple Myeloma (MM) patients (pts) with high ALCpeak treated with prophylactic dexamethasone (PPX DEX) at Mayo Clinic since 12/2024.</div></div><div><h3>Methods</h3><div>Retrospective analysis of 102 pts (new cohort) treated with cilta-cel between 12/2024-05/2025 after the introduction of PPX DEX using an oral 10mg bid dose for at least three days in pts with high ALCpeak (>3x10^9/L). This is compared to 230 pts who received cilta-cel between 02/2022 -11/2024 (historical cohort) where PPX DEX was not used.</div></div><div><h3>Results</h3><div>No significant differences were seen in pre-infusion disease burden, rates of all/high-grade CRS or ICANS, IEC-HS and tocilizumub use in the new vs historical cohorts. The new cohort had a median follow-up of 3.6 months where high ALCpeak was observed in 49 (48%) pts of which DNT was observed in 11 (22%) pts: 3 (6%) IEC-PKS and 8 (16%) IEC-NP. DNT was observed in 1 (2%) pt with ALCpeak <3x10^9/L who developed IEC-NP. In the new cohort, 43 (42%) pts received DEX (34 PPX DEX and 9 treatment DEX). Among DEX-treated pts, DNT was observed in 8 (19%) pts; 2 (5%) IEC-PKS, 6 (14%) IEC-NP. DNT rates between pts receiving DEX for high ALCpeak were compared against the historical cohort with high ALCpeak (n=97). Estimated 90-day DNT by Kaplan-Meier method was (19% vs 21%; p=0.49): IEC-PKS (5% vs 7%; p=0.46) and IEC-NP (16% vs 13%; p=0.96). The use of DEX did not significantly reduce the risk of DNT (HR 0.76, 95% CI: 0.34-1.70), IEC-PKS (HR 0.57, 95% CI: 0.12-2.64) or IEC-NP (0.98, 95% CI: 0.37-2.55) vs the historical cohort.</div><div>ALC expansion over the first month post CAR-T infusion (area under the curve, AUC) was next assessed. No difference in median AUC was seen in pts receiving DEX vs the historical cohort with high ALCpeak (37 vs 44, p=0.13). Amongst pts receiving DEX, median AUC was not different between pts who developed DNT vs those who did not (71 vs 30, p=0.16)</div><div>Among pts with DNT, no differences were observed in the severity of presentation between pts who received PPX DEX vs DNT cases from the historical cohort. Two of 3 IEC-PKS had PPX DEX but presented with severe symptoms; non-responsive to methylprednisolone, intrathecal chemotherapy and high-dose cyclophosphamide. Both pts subsequently died from sepsis.</div></div><div><h3>Conclusion</h3><div>While ALCpeak >3x10^9/L predicts risk of DNT in pts treated with cilta-cel, the use of DEX neither reduc","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"32 2","pages":"Page S12"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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